Synthesis of C-aryl-nucleosides and O-aryl-glycosides via cuprate glycosylation

Article abstract of DOI:10.1021/jo7016185

(Chemical Equation Presented) 2′-Deoxy-C-aryl-nucleosides have found increasing importance in studying DNA-DNA and DNA-protein interactions, as unnatural DNA-base pairs, and as oligonucleotide based fluorophores. Access to the required C-aryl-nucleosides

Full text of DOI:10.1021/jo7016185

Synthesis of C-Aryl-Nucleosides and O-Aryl-Glycosides via Cuprate
Glycosylation
Sven Hainke, Ishwar Singh, Jennifer Hemmings, and Oliver Seitz*
Humboldt-UniVersita¨t zu Berlin, Institut fu¨r Chemie, Brook-Taylor Strasse 2, D-12489 Berlin, Germany
oliVer.seitz@chemie.hu-berlin.de
ReceiVed July 24, 2007
2′-Deoxy-C-aryl-nucleosides have found increasing importance in studying DNA-DNA and DNA-
protein interactions, as unnatural DNA-base pairs, and as oligonucleotide based fluorophores. Access to
the required C-aryl-nucleosides is provided by several glycosylation methods. Though useful in many
cases, these methods often have drawbacks such as low yields or low economic efficiency. The necessity
for intensive optimization of the reaction conditions and/or the use of hazardous and toxic reagents can
render C-glycosylation reactions cumbersome. Herein we describe a robust and highly efficient
C-glycosylation method. It is shown that aryl cuprates of the Normant-type reliably react with Hoffer’s
chlorosugar to deliver C-aryl-nucleosides in up to 93% yield. This method may substitute for the previously
employed coupling with organocadmium or -zinc species. Peculiar reactivities are reported for
C-glycosylation of Gilman-type aryl cuprates which required substantial arene-specific optimization.
Interestingly, the glycosylation of Gilman cuprates was found to provide access not only to C-aryl-
nucleosides but also to O-aryl-glycosides. The reactions of Gilman cuprates with Hoffer’s chlorosugar 1
in the presence of oxygen provided the coresponding O-aryl-2′-deoxyribosides in up to 87% yield without
concomitant C-glycosylation.
Introduction
these methods often have drawbacks such as low yields or
economic efficiency, the necessity for intensive optimization
of the reaction conditions, and/or the use of hazardous and
environmentally toxic reagents. For example, the coupling of
lithium organyls to ribonolactons is a widely applicable method
but it requires the use of an expensive glycosyldonor to improve
the typically low yields.10-12 Costly glycosyl donors and time-
consuming arene-specific optimizitation are required in â-selec-
Aromatic analogues of DNA nucleobases have become
valuable tools in studies of DNA-DNA and DNA-protein
interactions.1 Designed C-aryl-nucleosides have been incorpo-
rated as base surrogates into DNA to study base stacking
interactions,2 to enable new base pairing modes,3,4 and to probe
the reaction mechanisms of DNA-polymerases5 and DNA-repair
enzymes.6 We have used C-glycosidically linked bulky arenes
in studies of the base flipping mechanism of DNA-methyltrans-
ferases.7,8 Synthetic access of the C-aryl-nucleosides is provided
by a variety of methods, which differ in the coupling chemistry
used to achieve the critical coupling of the aryl moiety with
the 2-deoxyribose backbone.9 Though useful in many cases,
(3) (a) Berger, M.; Luzzi, S. D.; Henry, A. A.; Romesberg, F. E. J. Am.
Chem. Soc. 2002, 124, 1222-1226. (b) Henry, A. A.; Yu, C. Z.; Romesberg,
F. E. J. Am. Chem. Soc. 2003, 125, 9638-9646. (c) Lai, J. S.; Kool, E. T.
J. Am. Chem. Soc. 2004, 126, 3040-3041. (d) Matsuda, S.; Romesberg, F.
E. J. Am. Chem. Soc. 2004, 126, 14419-14427. (e) Dupradeau, F. Y.; Case,
D. A.; Yu, C. Z.; Jimenez, R.; Romesberg, F. E. J. Am. Chem. Soc. 2005,
127, 15612-15617. (f) Lee, A. H. F.; Kool, E. T. J. Org. Chem. 2005, 70,
132-140. (g) Hwang, G. T.; Romesberg, F. E. Nucleic Acids Res. 2006,
34, 2037-2045. (h) Leconte, A. M.; Matsuda, S.; Romesberg, F. E. J. Am.
Chem. Soc. 2006, 128, 6780-6781. (i) Leconte, A. M.; Matsuda, S.; Hwang,
G. T.; Romesberg, F. E. Angew. Chem., Int. Ed. 2006, 45, 4326-4329. (j)
Lee, A. H. F.; Kool, E. T. J. Am. Chem. Soc. 2006, 128, 9219-9230. (k)
Matsuda, S.; Henry, A. A.; Romesberg, F. E. J. Am. Chem. Soc. 2006,
128, 6369-6375. (l) Matsuda, S.; Leconte, A. M.; Romesberg, F. E. J.
Am. Chem. Soc. 2007, 129, 5551-5557.
(1) For reviews see: (a) Kool, E. T. Acc. Chem. Res. 2002, 35, 936-
943. (b) Krueger, A. T.; Lu, H. G.; Lee, A. H. F.; Kool, E. T. Acc. Chem.
Res. 2007, 40, 141-150. (c) Henry, A. A.; Romesberg, F. E. Curr. Opin.
Chem. Biol. 2003, 7, 727-733. (d) Rist, M. J.; Marino, J. P. Curr. Org.
Chem. 2002, 6, 775-793.
(2) (a) Brotschi, C.; Mathis, G.; Leumann, C. J. Chem. Eur. J. 2005, 11,
1911-1923. (b) Lai, J. S.; Qu, J.; Kool, E. T. Angew. Chem., Int. Ed. 2003,
42, 5973-5977.
10.1021/jo7016185 CCC: $37.00 © 2007 American Chemical Society
Published on Web 10/17/2007
J. Org. Chem. 2007, 72, 8811-8819
8811

Hainke et al.
tive coupling chemistries which draw upon reactions of arylpal-
ladium species with a glycal13,3e and of organoaluminium
reagents with an 1,2-anhydrosugar.14 Rapid and cost-efficient
access to C-nucleosides is provided by Friedel-Crafts-alkyla-
tion.15 However, this method is limited to electron-rich arenes.
The most frequently applied general route to C-aryl-nucleosides
involves the use of Hoffer’s chlorosugar16 1 (1,2-dideoxy-3,5-
di-O-(p-toluoyl)-R-1-chloro-D-ribofuranose) and an aryl metal
species. The direct use of aryl Grignard17 and aryl lithium
reagents is plagued by concomitant elimination at the glycosyl
donor. Transmetalation to cadmium is a commonly applied
means to reduce the basicity of the aryl nucleophile.7,18,19
Cadmium organyls are highly toxic and exhibit relatively modest
reactivity. Our group and the Carell group have reported
preliminary studies on the C-ribosylation of aryl cuprates.4a,8
However, these studies were focused on the properties of base-
modified oligonucleotides rather than on synthesis. Neither has
the cuprate type, which is known to critically affect their
reactivity,20 been varied, nor have scope and limitations of
cuprate glycosylation been investigated. In pursuit of providing
robust and efficient access to C-aryl-nucleosides we became
(4) (a) Clever, G. H.; Polborn, K.; Carell, T. Angew. Chem., Int. Ed.
2005, 44, 7204-7208. (b) Clever, G. H.; Soltl, Y.; Burks, H.; Spahl, W.;
Carell, T. Chem. Eur. J. 2006, 12, 8708-8718. (c) Clever, G. H.; Carell,
T. Angew. Chem., Int. Ed. 2007, 46, 250-253.
(5) (a) Moran, S.; Ren, R. X. F.; Rumney, S.; Kool, E. T. J. Am. Chem.
Soc. 1997, 119, 2056-2057. (b) Moran, S.; Ren, R. X. F.; Kool, E. T.
Proc. Natl. Acad. Sci. U.S.A. 1997, 94, 10506-10511. (c) Morales, J. C.;
Kool, E. T. Nat. Struct. Biol. 1998, 5, 950-954. (d) Kool, E. T.; Morales,
J. C.; Guckian, K. M. Angew. Chem., Int. Ed. 2000, 39, 990-1009.
(6) (a) Jiang, Y. L.; Stivers, J. T.; Song, F. H. Biochemistry 2002, 41,
11248-11254. (b) Krosky, D. J.; Song, F. H.; Stivers, J. T. Biochemistry
2005, 44, 5949-5959.
(7) Singh, I.; Hecker, W.; Prasad, A. K.; Virinder, S. P. A.; Seitz, O.
Chem. Commun. 2002, 500-501.
FIGURE 1. Structure of C-aryl-nucleosides synthesized by glycosy-
lation of aryl cuprates.
(8) Beuck, C.; Singh, I.; Bhattacharya, A.; Heckler, W.; Parmar, V. S.;
Seitz, O.; Weinhold, E. Angew. Chem., Int. Ed. 2003, 42, 3958-3960.
(9) Wu, Q. P.; Simons, C. Synthesis 2004, 1533-1553.
interested in exploring the utility of different cuprate reagents.
Specifically, we investigated the reactivity of lithium- and
magnesium-based aryl cuprates in C-glycosylations with Hof-
fer’s chlorosugar 1. We herein provide full experimental details
and demonstrate that Normant-type aryl cuprates allow for both
highly reliable and highly efficient syntheses of polycyclic
C-aryl-nucleosides (Figure 1). To our surprise we noticed that
minor changes of the reaction conditions enable efficient access
of O-aryl-glycosides which are more difficult to synthesize by
using conventional Lewis acid-mediated glycosylation reactions.
(10) Wichai, U.; Woski, S. A. Org. Lett. 1999, 1, 1173-1175.
(11) Urban, M.; Pohl, R.; Klepetarova, B.; Hocek, M. J. Org. Chem.
2006, 71, 7322-7328.
(12) Zahn, A.; Brotschi, C.; Leumann, C. J. Chem. Eur. J. 2005, 11,
2125-2129.
(13) (a) Farr, R. N.; Outten, R. A.; Cheng, J. C. Y.; Daves, G. D.
Organometallics 1990, 9, 3151-3156. (b) Li, J. S.; Chen, F. X.; Shikiya,
R.; Marky, L. A.; Gold, B. J. Am. Chem. Soc. 2005, 127, 12657-12665.
(c) Sun, Z.; Ahmed, S.; McLaughlin, L. W. J. Org. Chem. 2006, 71, 2922-
2925.
(14) Singh, I.; Seitz, O. Org. Lett. 2006, 8, 4319-4322.
(15) (a) Hainke, S.; Arndt, S.; Seitz, O. Org. Biomol. Chem. 2005, 3,
4233-4238. (b) Aketani, S.; Tanaka, K.; Yamamoto, K.; Ishihama, A.; Cao,
H. H.; Tengeiji, A.; Hiraoka, S.; Shiro, M.; Shionoya, M. J. Med. Chem.
2002, 45, 5594-5603. (c) Aubert, Y.; Asseline, U. Org. Biomol. Chem.
2004, 2, 3496-3503. (d) Hatano, A.; Makita, S.; Kirihara, M. Bioorg. Med.
Chem. Lett. 2004, 14, 2459-2462.
Results and Discussion
Glycosylation. The usefulness of copper-based reagents for
the synthesis of C-glycosides has been demonstrated first by
Bihovsky, who reported the coupling of methyl- and phenyl-
Gilman cuprates with R-glycopyranosylbromides.21 Subse-
quently, anomeric pyranosyl esters22 and 1,2-anhydropyranoses23
have been shown to react with aromatic and aliphatic cuprates.
Surprisingly, prior to our preliminary report8 cuprates have not
been used for the synthesis of C-linked furanosides such as
2-deoxy-C-aryl-nucleosides. Our first attempt in subjecting aryl
cuprates to C-glycosylation reactions with chlorosugar 1 was
(16) Hoffer, M. Chem. Ber. 1960, 93, 2777-2781.
(17) (a) Schweitzer, B. A.; Kool, E. T. J. Org. Chem. 1994, 59, 7238-
7242. (b) Chen, D. W.; Beuscher, A. E.; Stevens, R. C.; Wirsching, P.;
Lerner, R. A.; Janda, K. D. J. Org. Chem. 2001, 66, 1725-1732. (c) Hashmi,
S. A. N.; Hu, X.; Immoos, C. E.; Lee, S. J.; Grinstaff, M. W. Org. Lett.
2002, 4, 4571-4574.
(18) Ren, R. X. F.; Chaudhuri, N. C.; Paris, P. L.; Rumney, S.; Kool, E.
T. J. Am. Chem. Soc. 1996, 118, 7671-7678.
(19) (a) Wang, Z. X.; Duan, W. L.; Wiebe, L. I.; Balzarini, J.; De Clercq,
E.; Knaus, E. E. Nucleosides Nucleotides Nucleic Acids 2001, 20, 11-40.
(b) Tilquin, J. M.; Dechamps, M.; Sonveaux, E. Bioconj. Chem. 2001, 12,
451-457. (c) Pirrung, M. C.; Zhao, X. D.; Harris, S. V. J. Org. Chem.
2001, 66, 2067-2071. (d) Issa, W.; Tochon-Danguy, H. J.; Lambert, J.;
Sachinidis, J. I.; Ackermann, U.; Liu, Z.; Scott, A. M. Nucl. Med. Biol.
2004, 31, 839-849.
(21) Bihovsky, R.; Selick, C.; Giusti, I. J. Org. Chem. 1988, 53, 4026-
4031.
(20) Modern Organocopper Chemistry; Krause, N., Ed.; Wiley-VCH:
Weinheim, Germany, 2002. Organocopper Reactions; Taylor, R. J. K., Ed.;
Oxford University Press: Oxford, UK, 1994. Sengupta, S.; Lipschutz, B.
H. Org. React. 1992, 41, 135-631.
(22) Bolitt, V.; Mioskowski, C.; Falck, J. R. Tetrahedron Lett. 1989,
30, 6027-6030.
(23) Bellosta, V.; Czernecki, S. J. Chem. Soc., Chem. Commun. 1989,
199-200.
8812 J. Org. Chem., Vol. 72, No. 23, 2007

Synthesis of C-Aryl-Nucleosides and O-Aryl-Glycosides
TABLE 1. Reagents, Conditions, and Yields of Several Cuprate Reactions
anomeric
selectivity R:â
yield,
%
entry
product
cuprate
arene
1-bromopyrene
1-bromopyrene
1-bromopyrene
3-bromotoluene
3-bromotoluene
3-bromotoluene
1-bromopyrene
1-bromopyrene
1-bromopyrene
1-bromopyrene
2-bromobiphenyl
3-bromobiphenyl
1-bromophenanthrene
4-bromo[1,1′]binaphthyl
2-bromo(7-phenyl)naphthalene
2-iodoanthracene
conditions
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
4a
4a
4a
4b
4b
4b
4a
4a
4a
4a
4c
4d
4e
4f
Ar2CuMgBr
Ar2CuMgBr
Ar2CuMgBr
Ar2CuMgBr
Ar2CuLi
Ar2CuLi
Ar2CuLi
Ar2CuLi
Ar2Cu(CN)Li2
ArCu(CN)ZnI
Ar2CuMgBr
Ar2CuMgBr
Ar2CuMgBr
Ar2CuMgBr
Ar2CuMgBr
Ar2CuLi
1 h; -10 °C to rt
1 h; 40 °C
1 h; 60 °C
4:1
3:1
2.3:1
1.5:1
4:1
75
93
86
87
63
40
22
69
63
39
83
73
80
75
76
47
1 h; 40 °C
18 h, -18 °C to rt
18 h, -40 °C
18 h; -18 °C to rt
18 h; -78 °C to rt
18 h; 0 °C to rt
18 h; 0 °C to rt
1 h; 40 °C
1 h; 40 °C
1 h; 40 °C
1 h; 40 °C
1 h; 40 °C
4:1
>20:1
>20:1
>20:1
>20:1
1:1.3
1.6:1
3:1
3:1
1:1.5
>20:1
4g
4h
18 h, -25 °C
SCHEME 1. Synthesis of C-Aryl-Nucleosides
based on the use of Normant cuprates which were prepared from
the aryl Grignard reagents via treatment with 0.5 equiv of copper
iodide. A subsequent report from Carell and co-workers
suggested the usefulness of Gilman cuprates.4a We therefore
decided to explore the reactivity of both Normant and Gilman
cuprates in the synthesis of C-aryl-nucleosides.
Our first aim was to optimize the coupling of Normant
cuprates with Hoffer’s chlorosugar 1. The pyrene nucleoside
2a18 was chosen as a representative example. The Grignard
reagent 1-pyrenylmagnesium bromide was prepared in THF
from 1-bromopyrene 3a and subjected to transmetallation with
copper iodide. The C-glycosylation was commenced upon
addition of chlorosugar 1. The bis-toluoyl-protected nucleoside
4a was obtained as a mixture of â-epimer 4aâ and R-epimer
4aR in 74% yield when the reaction was performed for 1 h at
-10 °C (entry 1, Table 1). Increases of the reaction temperature
to 40 °C resulted in significant increases of coupling yield
(93%) and changes of the R/â-anomer ratio from 4:1 to 3:1
(entry 2, Table 1). The reaction still proceeded remarkably well
at 60 °C furnishing 4a in slightly reduced 86% yield and higher
content of the â-anomer (R:â ) 2.3:1). Other alterations of the
reaction conditions such as the use of cosolvents like 1,4-
dioxane, dichloromethane, and toluene or the exclusion of
iodide ions by omitting iodine etching of magnesium and using
copper bromide-dimethyl sulfide instead of copper iodide had
little effect on reaction yields or selectivities (data not
shown). The optimized conditions were further evaluated in
the synthesis of 3-tolyl nucleoside 4b.10 The use of Normant
cuprate (3-tolyl)2CuMgBr, synthesized from 3-bromotoluene
3b, provided for a smooth reaction and delivered 4b in 87%
yield. Notably, the yields furnished by the cuprate method
are higher than the yields reported for the reactions of the
corresponding aryl cadmium (4a, 72%)8 and aryl lithium
derivatives (4b, 35%)10 with chlorosugar and ribonolactone,
respectively.
resulted in the formation of the O-glycoside 5a (vide infra).
The use of carefully degassed THF solved the problem of
O-glycoside formation; however, it reduced the efficiency of
C-glycosylation to 40% synthesis yield (entry 6, Table 1). The
attempt to synthesize the 1-pyrenyl-C-nucleoside 4a by using
the Gilman cuprate and applying the reaction conditions
optimized for the synthesis of 3-tolyl-C-nucleoside 4b failed
to provide useful synthesis yields (entry 7, Table 1). In this
case it proved necessary to reduce the reaction temperature to
-78 °C (entry 8, Table 1). Under these conditions 4a was
obtained in 69% yield with high R-selectivity (R:â ) >20:1).
The use of the higher order cyanocuprate (1-pyrenyl)2Cu(CN)-
Li2 or the zinc copper reagent (1-pyrenyl)Cu(CN)ZnI did not
result in enhancements of reaction yields (entries 9 and 10, Table
1). In these reactions the formation of the R-epimer was highly
favored.
The results discussed above suggested that the use of
Normant-type aryl cuprates provides for higher robustness and
synthesis yields than the use of Gilman-type aryl cuprates. For
further exploration the C-glycosylation of cuprates was tested
in the synthesis of additional C-aryl-nucleosides which were
required in an ongoing project toward mechanistical studies of
base flipping DNA-methyltransferases. Precursors for the 2-bro-
mobiphenyl nucleoside 2c and the 3-bromobiphenyl nucleoside
2d, 2-bromobiphenyl 3c and 3-bromobiphenyl 3c, were com-
mercially available. The “aglycon units” of C-aryl-nucleosides
2e and 2h, 1-bromophenanthrene 3e and 2-iodoanthracene 3h,
We next studied cuprates that were synthesized from lithium
organyls via transmetallation with copper iodide. The 3-tolyl-
based Gilman cuprate was allowed to react with chlorosugar 1.
In the optimization process, we noticed that the reactions
proceeded more slowly, requiring lower reaction temperatures
and longer reaction times of up to 18 h than the C-glycosylation
reactions of Normant cuprates. In addition, rather peculiar
reactivities were observed. The highest yield (63%) was obtained
when the reaction was performed at -18 °C in THF (entry 5,
Table 1). The reduction of reaction temperature to -40 °C
J. Org. Chem, Vol. 72, No. 23, 2007 8813

Hainke et al.
SCHEME 2. Synthesis of 4-Bromo[1,1′]binaphthyl 3f and
SCHEME 3. Synthesis of O-Aryl-Glycosides
2-Bromo(7-phenyl)naphthalene 3g
delivered the 3-tolyloxy-2′-deoxyriboside 5a (R:â ) 2.5:1, 87%)
and the 2-anthracenyloxy-2′-deoxyriboside 5b (R:â ) 4:1; 80%)
in surprisingly high yields after purification. O-aryl-glycoside
structures are found in several natural products like vancomycin,
chromomycin, and olivomycin.31 Their synthesis is usually a
quite demanding task that requires careful optimization of the
reaction conditions.32 A typical problem in the most commonly
applied Lewis acid-promoted O-glycosylation of arylalcohols
is the concurrent formation of C-linked aryl-glycosides. In
contrast, glycosylation of Gilman cuprates with 1 under aerobic
conditions at low temperatures (e-40 °C) provided the O-aryl-
nucleosides 5 without concomitant C-glycosylation.
Structure Verification. The structures of the newly synthe-
sized nucleosides were verified by 1H NMR,13C NMR, and 1H-
1H NOESY-NMR spectroscopy and HRMS. The NOESY
spectrum of the â-anomers 4c-e, 4f, and 2g showed in all cases
characteristic interactions between H1′ and H2′R and also H3′
and H2′â, which confirmed the anomeric configuration. In the
case of the 2-biphenyl nucleoside 2bâ the NMR signals of H2′R
and H2′â overlap. Hence the NOESY spectrum of the un-
naturally configured R-anomeric C-nucleoside 2bR was used
to confirm the structure of the nucleoside wherein H2′â shows
predominant interactions with H1′ and H3′. The NMR spectra
of the anomerically pure binaphthyl nucleoside 2f exposed the
existence of two different diastereomers. The [1,1′]binaphthyl
group provides axial chirality. The energy barrier for rotation
around the binaphthyl bond was, however, not sufficient to allow
separation by reversed phase-HPLC at ambient temperature. The
structures of the O-glycosides 5 were confirmed by HRMS, 1H
NMR, 1H,1H NOESY-NMR, and 13C NMR. The low field shift
of the anomeric carbon atoms (δ 102-103 ppm) indicated the
presence of an O-glycoside structure rather than a C-glycoside
(δ 78-81 ppm).
were synthesized according to literature procedures.24,25 The
naphthyl-based aryl-nucleosides 2f and 2g were prepared by
glycosylation of cuprates from aryl bromides 3f and 3g. The
latter were assessed by coupling 1-naphthylboronic acid with
1,4-dibromonaphthalene26 6 or phenylboronic acid with 2,7-
dibromonaphthalene27 7 at Suzuki coupling conditions28,29
(Scheme 2).
The aryl bromides 3c-e, 3f, and 3g were converted to
Normant cuprates and used in C-glycosylation reactions with
chlorosugar 1 at conditions which were identified during the
optimization of the coupling of pyrene cuprates. The reaction
delivered the desired products in reliable 73-86% yield after
purification (entries 11-15, Table 1). We note that these yields
were obtained at the first attempt without further arene-specific
optimization, which attests to the robustness of Normant cuprate-
mediated C-glycosylation. The anomers were usually separated
at the O-protected stage via flash chromatography. However,
the R- and â-form of 2-biphenyl nucleoside 4c exhibited
identical Rf-values. In this case, the anomers were separated
after deacylation. For the synthesis of 2-anthracenyl-C-nucleo-
side30 4h we resumed the use of Gilman cuprates since the
2-iodoanthracene 3h is not amenable to Grignard reaction. Thus,
lithiation had to be employed to provide access to a cuprate.
The coupling of 3h with chlorosugar 1 again required substantial
optimization to deliver purified 4h in 47% yield. During the
optimization process we noticed the formation of an additional
product that coeluted in flash chromatography with the C-
nucleoside but showed additional signals in the NMR spectra.
The new product was the sole product when the reaction of the
Gilman cuprate with 1 was performed at temperatures below
-40 °C in not perfectly degassed THF. NMR spectroscopy and
high-resolution mass spectrometry revealed the O-aryl-glycoside
structure 5. After the identification of the new product, the
cuprate-mediated glycosylation was carried out under air instead
of an argon atmosphere by using 3-bromotoluene and 2-iodo-
anthracene precursors. The reactions proceeded smoothly and
Epimerization and Deprotection. The cuprate-mediated
glycosylation reactions provided the C-aryl-nucleosides as a
mixture of anomers. Often the R-anomer was favored. Acid-
mediated epimerization was used to enrich the thermodynami-
cally slightly favored â-anomers. We applied conditions reported
by Stivers and co-workers and employed trifluoroactic acid
(TFA) or TFA/benzenesulfonic acid (5:1 v:w) in dichloro-
methane to promote epimerization.33 In general, the more
electron-rich arenes required smaller amounts of promotor. For
example, 4a, having an electron-rich 1-pyrenyl substructure,
epimerized in the presence of a 1% solution of TFA. In contrast,
(24) Harrowven, D. C.; Guy, I. L.; Nanson, L. Angew. Chem., Int. Ed.
2006, 45, 2242-2245.
(25) House, H. O.; Koepsell, D.; Jaeger, W. J. Org. Chem. 1973, 38,
1167-1173.
(26) Cakmak, O.; Demirtas, I.; Balaydin, H. T. Tetrahedron 2002, 58,
5603-5609.
(27) Neenan, T. X.; Whitesides, G. M. J. Org. Chem. 1988, 53, 2489-
2496.
(31) Weymouth-Wilson, A. C. Nat. Prod. Rep. 1997, 14, 99-110.
(32) Jacobsson, M.; Malmberg, J.; Ellervik, U. Carbohydr. Res. 2006,
341, 1266-1281.
(33) (a) Jiang, Y. L.; Stivers, J. T. Tetrahedron Lett. 2003, 44, 85-88.
(b) Jiang, Y. L.; Stivers, J. T. Tetrahedron Lett. 2003, 44, 4051-4055.
(28) Scherf, U.; Mu¨llen, K. Synthesis 1992, 23-38.
(29) Wipf, P.; Jung, J. K. J. Org. Chem. 2000, 65, 6319-6337.
(30) Coleman, R. S.; Mortensen, M. A. Tetrahedron Lett. 2003, 44,
1215-1219.
8814 J. Org. Chem., Vol. 72, No. 23, 2007

Synthesis of C-Aryl-Nucleosides and O-Aryl-Glycosides
TABLE 2. Reagents, Conditions, and Yields of Epimerization and Deprotection Reactions
toluoyl
ester
starting
ratio R:â
product
ratio R:â
yield, %
(isolated â-anomer)
deprotection
product
yield,
%
entry
epimerization conditionsa
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
1% TFA
10% TFA/PhSO3H
3:1
1.5:1
1:2.3
1:2.4
57
52
2a
2b
2c
2d
2e
2f
91
92
81
70
79
70
93
57
18% TFA/PhSO3H
6% TFA/PhSO3H
6% TFA/ PhSO3H
12% TFA/PhSO3H
5% TFA
1.6:1
3:1
3:1
Pure R
>20:1
1:2.6
1:2.1
1:1.5
1:3.9
1:2.6
59
58
47
46
44
4g
4h
2g
2h
a In dichloromethane at 40 °C.
the comparatively electron-poor meta-substituted nucleosides
4b and 4d required 10% and 18% solutions of a more effective
TFA/benzensulfonic acid promotor (Table 2).34 After two
epimerization cycles the â-anomers were isolated in up to 70%
yield. For the synthesis of the O-unprotected C-aryl-nucleosides
2, the toluoyl protecting groups were removed by treatment of
4a-hâ with sodium methoxide in dry methanol by applying
conditions known in literature.18 After column chromatography
the corresponding unprotected C-nucleosides 4a-h were ob-
tained in high yields. The 2-biphenyl nucleoside 4cR/â was
deprotected as the anomeric mixture and then separated by using
preparative reversed phase-HPLC to yield the pure anomers
2cR/â and 2cR/â.
yield.17 The use of the corresponding cadmium- and zinc
organyls allowed 40-80% yield with electron-rich arylhalo-
genides providing higher yields than electron-poor precur-
sors.7,18,19 The results described in this study demonstrated the
beneficial reactivity of organocuprates which reacted faster and
delivered higher yields than previously used organometal
compounds. Although several types of cuprates were effective,
the most successful method relied on the use of Normant
cuprates. The use of Gilman cuprates required careful optimiza-
tion of reaction conditions. The cuprate method should also offer
a versatile strategy for the synthesis of functionalized C-aryl-
nucleosides. Carrell and co-worker have shown the cuprate-
mediated synthesis of C-nucleosides featuring formyl and
hydroxyl functional groups.4 Recent work by Knochel allows
access to a broad range of functionalized aryl magnesium
compounds using isopropylmagnesium chloride for halogen/
magnesium-exchange and their utility in copper-mediated reac-
tions has been demonstrated.35 C-Aryl-nucleosides bearing, for
example, nitrile, ester, or amide functions or several heterocyclic
C-aryl-nucleosides should be available after a halogen/magnesium-
exchange and further transmetallation to Normant cuprates.
Interestingly, the glycosylation of Gilman cuprates was found
to provide access not only to C-aryl-nucleosides but also to
O-aryl-glycosides. There are only a few examples in which
arylhalogenides have been used for the synthesis of O-aryl-2′-
deoxyribosides. In one, an organozinc reagent has been shown
to furnish the product of O-glycosylation in 19% yield.36 The
reactions of Gilman cuprates with Hoffer’s chlorosugar 1 in the
presence of oxygen provided the coresponding O-aryl-2′-
deoxyribosides 5 in up to 87% yield, which expands the
versatility of the cuprate glycosyation method.
Many powerful methods have been developed to improve the
critical C-C-coupling step in the synthesis of C-aryl-nucleo-
sides. Most attractive methods use inexpensive, readily available
starting materials and require little optimization and as few
synthetic steps as possible. Unparalled rapid access to C-aryl-
nucleosides (4 steps) is provided by the Friedel-Crafts-like
glycosylation, but the limitation to electron-rich arenes restricts
the general applicability of this method.15 By contrast, the
coupling of disiloxane-protected ribonolactone to aryllithiums
is widely applicable.10,11 The critical C-C-coupling has been
reported to occur in up to 56% yield; however, a modest 17%
yield has been reported for the C-glycosylation of sterically
hindered 2-substituted arenes.10 The described glycosylation of
cuprates with Hoffer’s chlorosugar combines general applicabil-
ity with conciseness (6 steps) and high synthetic efficiency
affording up to 93% C-C-coupling yield when Normant
cuprates are used. Remarkably, coupling of sterically hindered
arenes such as 2-bromobiphenyl 2c still proceeded in 83% yield.
Cuprate-mediated reactions occur under almost neutral condi-
tions which is advantageous with regard to the general ap-
plicability. For example, one may envision new entries to the
modular synthesis of multicyclic ring systems as described by
Hocek and co-workers.11,34 One drawback of the nonacidic
reaction medium is the resulting bias to the formation of
R-diastereomers. Nevertheless, the combined yields of C-C-
coupling and subsequent epimerization still surpass those of
most other methods. We wish to note that in the few cases where
it is difficult to separate â- from R-anomers one may consider
the use of strictly â-selective routes such as the palladium-
catalyzed coupling of iodoarenes with glycals13 or the syn-
opening of 1,2-anhydroarabinose by arylaluminium reagents.14
These methods typically require more steps and involve the use
of expensive starting materials.
Experimental Section
4-Bromo[1,1′]binaphthyl (12).28 In an argon-flushed Schlenk
flask 1.40 g (5.0 mmol) of 1,4-dibromonaphthalene 10 and 0.95 g
(5.5 mmol) of 1-naphthylboronic acid were dissolved in 10 mL of
degassed toluene. After the addition of 10 mL of degassed 2 M aq
potassium carbonate solution and 143 mg (0.125 mmol) of Pd-
(PPh3)4 the solution was stirred for 24 h at 100 °C. The reaction
mixture was worked up after the addition of 10% aq NH4Cl by
extraction with 30 mL of CH2Cl2 (3×). The combined organic
layers were washed with a saturated aqueous solution of
NaHCO3 and brine and dried over anhydrous MgSO4 and solvent
was removed under reduced pressure. Flash chromatography
(cyclohexane) yielded 1.12 g (67%) of a colorless solid. Mp 135-
136 °C. MS(EI): m/z C20H13Br+ calcd 332.0 (M), found 332.0. 1H
The coupling reactions between Hoffer’s chlorosugar and
magnesium organyls have been reported to proceed in 22-57%
(35) Ila, H.; Baron, O.; Wagner, A. J.; Knochel, P. Chem. Commun. 2006,
583-593.
(36) Gao, J. M.; Strassler, C.; Tahmassebi, D.; Kool, E. T. J. Am. Chem.
Soc. 2002, 124, 11590-11591.
(34) Hocek, M.; Pohl, R.; Klepetarova, B. Eur. J. Org. Chem. 2005,
4525-4528.
J. Org. Chem, Vol. 72, No. 23, 2007 8815

Hainke et al.
NMR (300 MHz, CDCl3): δ 8.38 (d, J ) 8.7, 1H), 8.01-7.97 (m,
2H), 7.94 (d, J ) 8.1, 1H), 7.65-7.59 (m, 2H), 7.54-7.49 (m,
2H), 7.45-7.30 (m, 5H). 13C NMR (75 MHz, CDCl3): δ 138.6,
137.5, 134.1, 133.5, 132.7, 131.9, 129.5, 128.2, 128.1, 127.9, 127.4,
127.3, 127.2, 126.8, 126.3, 126.2, 125.9, 125.4, 122.6. Anal. Calcd
for C20H13Br: C, 72.09; H, 3.93; Br, 23.98. Found: C, 72.17; H,
4.26; Br, 23.22.
138.0, 129.7, 129.6, 129.1, 129.0, 128.3, 128.1, 127.0, 126.8, 126.2,
122.7, 82.1, 80.3, 77.4, 64.8, 40.3, 21.7, 21.5.
R,â-1′,2′-Dideoxy-3′,5′-di-O-toluoyl-1′-(2-biphenyl)ribofura-
nose (4cR/â). Compound 4cR/â (609 mg; 83%; R:â ) 1:1.3) was
synthesized from 1 (563 mg; 1.45 mmol) as a colorless oil. HRMS-
(EI): m/z C33H30O5+ calcd 506.2093 (M), found 506.2093. 1H NMR
(300 MHz, CDCl3): δ 7.99-7.16 (m, 17H), 5.53-5.45 (m, 1H,
H3′), 5.36 (dd, JH1′,H2′R ) 7.4, JH1′,H2′â ) 7.4, H1′(R-epimer)), 5.36
(dd, JH1′,H2′R ) 10.9, JH1′,H2′â ) 6.0, 1H, H1′(â-epimer)), 4.75-
4.71 (m, H4′(R-epimer)), 4.70-4.59 (m, H5′(â-epimer)), 4.52-
4.41 (m, H5′(R-epimer)), 4.35 (td, JH4′,H5′ ) 3.9, JH3′,H4′ ) 2.5,
H4′(â-epimer)), 2.70 (ddd, JH2′â,H2′R ) 14.1, JH1′,H2′â ) 7.2, JH3′,H2′â
) 7.2, H2′â (â-epimer)), 2.44 (s, 6H), 2.31-2.11 (m, H2′). 13C
NMR (75 MHz, CDCl3): δ 166.4, 166.2, 166.0, 144.0, 143.8, 143.7,
141.0, 140.8, 140.8, 140.7, 139.5, 138.0, 130.0, 129.8, 129.7, 129.3,
129.2, 129.1, 128.3, 128.1, 128.0, 127.8, 127.5, 127.3, 127.2, 125.8,
125.7, 83.4, 82.0, 81.0, 77.7, 77.6, 64.9, 64.9, 41.9, 40.8, 21.7.
R-1′,2′-Dideoxy-3′,5′-ditoluoyl-1′-(1-phenanthrenyl)ribofura-
nose (4eR). Compound 4dR/â (436 mg; 80%; R:â ) 3:1) was
synthesized from 1 (400 mg; 1.03 mmol) as a colorless oil. HRMS-
(EI): m/z C35H30O5+ calcd 530.2093 (M), found 530.2093. 1H NMR
(300 MHz, CDCl3): δ 8.75-8.70 (m, 2H), 8.09 (m, 2H), 7.94-
7.62 (m, 9H), 7.30 (d, J ) 8.5 Hz, 2H), 7.15 (d, J ) 8.5 Hz, 2H),
6.17 (t, J ) 5.7 Hz, 1H), 5.74-5.70 (m, 1H), 4.93-4.89 (m, 1H),
4.72-4.65 (m, 2H), 3.30-3.21 (m, 1H), 2.49-2.45 (m, 4H), 2.39
(s, 3H). 13C NMR (75 MHz, CDCl3): δ 166.4, 166.0, 143.9, 138.8,
131.4, 130.6, 129.8, 129.7, 129.2, 129.0, 128.5, 128.3, 127.1, 126.8,
126.7, 126.6, 126.1, 123.0, 122.9, 122.1, 121.6, 82.5, 78.2, 77.2,
64.7, 40.0, 21.7, 21.6.
2-Bromo(7-phenyl)naphthalene (13).29 In an argon-flushed
Schlenk flask 784 mg (2.74 mmol) of 2,7-dibromonaphthalene 11
and 419 mg (3.0 mmol) of phenylboronic acid were dissolved in
10 mL of degassed 1,4-dioxane. After the addition of 10 mL of
degassed 2 M aq Ba(OH)2 solution and 156 mg (0.137 mmol) of
Pd(PPh3)4 the solution was stirred for 24 h at 80 °C. The reaction
mixture was worked up after the addition of 10% aq NH4Cl by
extraction against 30 mL of CH2Cl2 (3×). The combined
organic layers were washed with a saturated aqueous solution of
NaHCO3 and brine and dried over anhydrous MgSO4 and solvent
was removed under reduced pressure. Flash chromatography
(cyclohexane) yielded 500 mg (65%) of a colorless solid. Mp 100-
101 °C. HRMS(EI): m/z C16H11Br+ calcd 282.0044 (M), found
1
282.0043. H NMR (300 MHz, CDCl3): δ 7.95 (s, 1H), 7.83 (s,
1H), 7.77 (d, J ) 9.0, 1H), 7.66-7.57 (m, 4H), 7.46-7.30 (m,
4H). 13C NMR (75 MHz, CDCl3): δ 140.6, 139.7, 134.8, 131.0,
130.2, 129.8, 129.5, 129.4, 129.3, 129.0, 128.4, 127.7, 127.5, 126.1,
124.8, 120.3.
Typical Procedure for Normant-Cuprate Mediated Synthesis
of C-Aryl-Nucleosides: Synthesis of 4dRâ. For the preparation
of aryl Grignard from 3-bromobiphenyl, magnesium (106 mg, 4.36
mmol) was activated for 1 h by iodine etching in a Schlenk tube
while stirring without solvent. Then 25 mL of THF and 715 µL of
3-bromobiphenyl (4.29 mmol) were added to the magnesium and
the mixture was stirred at 44 °C until consumption of magnesium.
The resulting solution was cooled to 0 °C before 425 mg (2.23
mmol) of copper iodide was added. The reaction mixture was
allowed to warm to 20 °C and stirred for 30 min until the copper
iodide had dissolved. The solution was heated to 40 °C and the
R-chlorosugar 1 (730 mg; 1.87 mmol) was added. The mixture was
stirred for 1 h at 40 °C. Workup was commenced by the addition
of a 10% aqueous solution of NH4Cl followed by extraction with
30 mL of CH2Cl2 (3×). The combined organic layers were washed
with a saturated aqueous solution of NaHCO3 (3×) and brine then
dried over anhydrous MgSO4 and solvent was removed under
reduced pressure. The product was purified on a silica gel column
with cyclohexane:ethyl acetate (19:1) to yield 726 mg (73%) of
4dR/â (R:â ) 1.6:1) as a colorless oil.
R-1′′,2′′-Dideoxy-3′′,5′′-ditoluoyl-1′′-(R,S-[1,1′]binaphthylen-
4-yl)ribofuranose (4fR). Compound 4fR/â (314 mg; 75%; R:â )
3:1) was synthesized from 1 (270 mg; 0.70 mmol) as a colorless
+
oil. HRMS(EI): m/z C41H34O5 calcd 606.2406 (M), found
1
606.2403. H NMR (300 MHz, CDCl3): δ 8.03-7.92 (m, 6H),
7.77 (d, J ) 8.0, 1H), 7.73 (d, J ) 8.0, 1H), 7.68-7.27 (m, 11H),
7.18 (d, J ) 7.8, 1H), 7.09 (d, J ) 8.0, 1H), 6.23-6.17 (m, 1H,
H1′), 5.78-5.73 (m, 1H, H3′), 4.98-4.91 (m, 1H, H4′), 4.77-
4.64 (m, 2H, H5′), 3.32-3.22 (m, 1H, H2′â), 2.63-2. 49 (m, 1H,
H2′R), 2.44 (s, 3H), 2.40 (s, 1.3H), 2.30 (s, 1.7H). 13C NMR (75
MHz, CDCl3): δ 166.5, 166.1, 166.1, 144.0, 144.0, 143.9, 138.5,
138.2, 138.1, 137.8, 133.5, 133.5, 133.1, 132.9, 132.9, 130.2, 129.9,
129.8, 129.8, 129.6, 129.2, 129.2, 129.1, 128.2, 128.1, 128.0, 127.9,
127.8, 127.7, 127.6, 127.4, 127.3, 127.1, 126.8, 126.8, 126.6, 126.1,
126.0, 126.0, 125.9, 125.7, 125.6, 125.6, 125.5, 125.3, 123.3, 123.3,
82.8, 82.4, 78.4, 78.1, 64.8, 64.8, 39.9, 39.8, 21.7, 21.7, 21.6.
R-1′,2′-Dideoxy-3′,5′-ditoluoyl-1′-(2-(7-phenyl)naphthyl)ribo-
furanose (4gR). Compound 4gR/â was synthesized from 1 (300
mg; 0.77 mmol). The fractions were separated to yield 129 mg
(30%) of compound 4gR and 197 mg (46%) of compound 4gâ.
HRMS(EI): m/z C37H32O5+ calcd 556.2250 (M), found 556.2250.
1H NMR (300 MHz, CDCl3): δ 8.03-7.98 (m, 4H), 7.93 (d, J )
8.6, 1H), 7.89 (d, J ) 8.50, 1H), 7.79-7.71 (m, 3H), 7.64 (d, J )
8.2, 2H), 7.56-7.48 (m, 3H), 7.44-7.38 (m, 1H), 7.27 (d, J )
8.0, 2H), 7.03 (d, J ) 8.0, 2H), 5.68 (ddd, J ) 6.5, 3.4, 3.4, 1H,
H3′), 5.59 (dd, JH1′,H2′R ) 7.5, JH1′,H2′â ) 5.6, 1H, H1′), 4.81 (td,
1H, JH4′,H5′ ) 4.8, JH3′,H4′ ) 2.8, H4′), 4.69-4.59 (m, 2H, H5′),
3.04 (ddd, JH2′R,H2′â ) 14.2, JH1′,H2′â ) 7.6, JH3′,H2′â ) 6.8, 1H, H2′â),
2.49-2.41 (m, 1H, H2′R), 2.44 (s, 3H), 2.33 (s, 3H). 13C NMR
(75 MHz, CDCl3): δ 166.5, 166.1, 144.0, 143.9, 141.1, 140.4,
138.9, 133.5, 132.0, 129.8, 129.7, 129.2, 129.0, 128.9, 128.2, 128.0,
127.4, 127.1, 126.7, 125.9, 125.6, 124.7, 124.0, 82.5, 80.5, 76.5,
64.7, 40.3, 21.7, 21.6.
R-1′,2′-Dideoxy-3′,5′-di-O-toluoyl-1′-(3-biphenyl)ribofura-
nose (4dR). HRMS(ESI): m/z C33H30O5Na+ calcd 529.1985 (M
+ Na+), found 529.1985. 1H NMR (300 MHz, CDCl3): δ 7.98 (d,
J ) 8.3, 2H), 7.67 (s, 1H), 7.67 (d, J ) 8.3, 2H), 7.60-7.56 (m,
2H), 7.45-7.34 (m, 5H), 7.23 (d, J ) 7.5, 2H), 7.08 (d, J ) 7.9,
2H), 5.63 (ddd, J ) 6.4, 3.8, 3.0, 1H, H3′), 5.43 (dd, JH1′,H2′â
)
7.3, JH1′,H2′R ) 5.8, 1H, H1′), 4.72 (td, JH4′,H5′ ) 4.8, JH3′,H4′ ) 2.9,
1H, H4′), 4.59 (m, 2H, H5′), 2.98 (ddd, JH2′R,H2′â ) 13.9, JH1′,H2′â
) 7.5, JH3′,H2′â ) 6.7, 1H, H2′â), 2.40 (s, 3H), 2.36 (s, 3H), 2.40-
2.36 (m, 1H, H2′R). 13C NMR (75 MHz, CDCl3): δ 166.5, 166.2,
143.9, 143.9, 143.0, 141.5, 141.2, 129.8, 129.7, 129.2, 129.0, 128.8,
128.7, 127.3, 127.3, 127.1, 126.8, 126.3, 124.7, 124.5, 82.3, 80.3,
76.4, 64.6, 40.4, 21.7, 21.7.
R-1′,2′-Dideoxy-3′,5′-di-O-toluoyl-1′-(3-tolyl)ribofuranose (4bR).
Compound 4bR/â (641 mg; 87%) was synthesized from 1 (645
+
mg; 1.667 mmol) as a colorless oil. HRMS(EI): m/z C28H28O5
calcd 444.1937 (M), found 444.1936. 1H NMR (300 MHz,
CDCl3): δ 8.01 (d, J ) 8.2, 2 H), 7.76 (d, J ) 8.2, 2 H), 7.31-
7.20 (m, 7H), 7.15-7.11 (m, 1H), 5.64 (ddd, 1H, J ) 6.8, 3.9, 3.0,
H3′, 1H), 5.37 (dd, JH1′,H2′â ) 6.8, JH1′,H2′R ) 6.8, 1H, H1′), 4.74
(td, 1H, JH4′,H5′ ) 4.7, JH3′,H4′ ) 2.9, H4′), 4.67-4.56 (m, 2H, H5′),
2.97 (ddd, JH2′R,H2′â ) 14.1, JH1′,H2′â ) 7.2, JH3′,H2′â ) 7.2, 1H, H2′â),
2.44 (s, 3H), 2.42 (s, 3H), 2.39 (s, 3H), 2.38-2.31 (m, 1H, H2′).
13C NMR (75 MHz, CDCl3): δ 166.3, 166.1, 143.9, 143.7, 142.2,
Typical Procedure for Gilman-Cuprate Mediated Synthesis
of C-Aryl-nucleosides: Synthesis of 4hR. In a dry argon-flushed
flask 2-iodoanthracene (1.8 g; 5.9 mmol.) was added to 20 mL of
dry THF and cooled to -78 °C. With use of a glass syringe, t-BuLi
in pentane (7.9 mL; 1.5 M; 11.8 mmol) was added dropwise and
the solution was stirred for 15 min. After addition of copper iodide
(562 mg; 2.95 mmol) the solution was allowed to warm while the
8816 J. Org. Chem., Vol. 72, No. 23, 2007

Synthesis of C-Aryl-Nucleosides and O-Aryl-Glycosides
CuI dissolved. After cooling to -25 °C the chlorosugar 1 (730
mg; 1.87 mmol) was subsequently added and the mixture was stirred
for 18 h at this temperature. For workup a 10% aqueous solution
of NH4Cl was added followed by extraction with 30 mL of CH2-
Cl2 (3×). The organic layers were washed with a saturated aqueous
solution of NaHCO3 (3×) and brine and dried over anhydrous
MgSO4 and solvent was removed under reduced pressure. The
product was purified on a silica gel column with cyclohexane:
ethylacetate (19:1) to yield 473 mg (47%) of 4hR as a yellowish
oil.
143.9, 143.8, 138.4, 136.3, 136.3, 133.5, 133.0, 133.0, 132.9, 132.9,
130.5, 129.8, 129.8, 129.3, 129.2, 129.2, 128.2, 128.1, 128.0, 127.9,
127.8, 127.7, 127.7, 127.5, 127.1, 127.0, 126.6, 126.6, 126.0, 125.9,
125.9, 125.8, 125.7, 125.4, 125.3, 123.2, 123.1, 122.0, 121.9, 82.7,
82.7, 78.2, 78.0, 64.7, 40.9, 40.8, 21.8, 21.7, 21.7.
â-1′,2′-Dideoxy-3′,5′-ditoluoyl-1′-(2-(7-phenyl)naphthyl)ribo-
furanose (4gâ). Epimerization of 4gR/â (129 mg; 0.23 mmol)
yielded 59 mg of 4gâ (46%) as a colorless foam and 15 mg of
mixed fractions of 4gR/â (12%). HRMS(EI): m/z C37H32O5+ calcd
1
556.2250 (M), found 556.2251. H NMR (300 MHz, CDCl3): δ
R-1′,2′-Dideoxy-3′,5′-di-O-toluoyl-1′-(2-anthracenyl)ribofura-
8.55 (s, 1H), 8.48 (s, 1H), 8.10 (d, J ) 8.2, 2H), 8.04-7.95 (m,
5H), 7.80 (d, J ) 6.9, 1H), 7.51-7.42 (m, 3H), 7.35 (d, J ) 8.1,
2H), 7.21 (d, J ) 8.1, 2H), 5.71 (d, 1H, J ) 6.2, H3′), 5.47 (dd,
nose (4hR). HRMS(EI): m/z C35H30O5+ calcd 530.2093 (M), found
1
530.2093. H NMR (300 MHz, CDCl3): δ 8.49 (s, 1H), 8.46 (s,
1H), 8.07 (d, J ) 8.1, 2H), 8.03-7.97 (m, 3H), 7.79 (d, J ) 6.9,
1H), 7.70 (d, J ) 8.1, 2H), 7.52-7.47 (m, 3H), 7.30 (d, J ) 8.0,
2H), 7.16 (d, J ) 8.0, 2H), 6.23 (dd, JH1′,H2′R ) 7.3, JH1′,H2′â ) 6.1,
1H, H1′), 5.75 (ddd, J ) 6.6, 3.4, 3.4, 1H, H3′), 4.92 (td, 1H, JH4′,H5′
) 4.7, JH3′,H4′ ) 2.9, H4′), 4.79-4.69 (m, 2H, H5′), 3.32 (ddd,
JH2′R,H2′â ) 14.4, JH1′,H2′â ) 7.3, JH3′,H2′â ) 7.3, 1H, H2′â), 2.53
(ddd, JH2′R,H2′â ) 13.6, JH1′,H2′R ) 5.6, JH3′,H2′R )3.6, 1H, H2′R),
2.46 (s, 3H), 2.39 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 166.5,
166.1, 144.0, 137.8, 132.0, 131.6, 131.3, 129.9, 129.7, 129.2, 129.0,
128.7, 128.5, 128.2, 127.9, 127.3, 127.2, 126.8, 125.7, 124.8, 121.9,
121.7, 82.4, 78.2, 76.5, 64.8, 39.7, 21.7, 21.7.
JH1′,H2′R ) 10.8, JH1′,H2′â ) 5.8, 1H, H1′), 4.84-4.67 (m, 2H, H5′),
4.65 (td, 1H, JH4′,H5′ ) 3.6, JH3′,H4′ ) 1.9, H4′), 2.65 (dd, JH2′R,H2′â
) 13.7, JH1′,H2′R ) 5.2, JH3′,H2′R ) 0.8, 1H, H2′R), 2.48 (s, 3H),
2.37 (s, 3H), 2.44-2.34 (m, 1H, H2′â). 13C NMR (75 MHz,
CDCl3): δ 166.5, 166.2, 144.2, 143.9, 141.0, 138.8, 138.8, 133.6,
132.3, 129.8, 129.8, 129.3, 128.9, 128.2, 128.1, 127.4, 127.1, 127.0,
125.9, 125.7, 125.1, 124.0, 83.2, 81.0, 77.4, 64.8, 42.0, 21.8, 21.6.
â-1′,2′-Dideoxy-3′,5′-di-O-toluoyl-1′-(3-tolyl)ribofuranose (4bâ).
Epimerization of 4gR/â (635 mg; 1.43 mmol) yielded 333 mg of
4gâ (52%) as a colorless foam and 128 mg of of 4gR (20%).
HRMS(ESI): m/z C28H28O5+ calcd 444.1937 (M), found 444.1936.
1H NMR (300 MHz, CDCl3): δ 8.03-7.97 (m, 4H), 7.32-7.22
(m, 7H), 7.13-7.10 (m, 1H), 5.64 (d, 1H, J ) 5.0, H3′, 1H), 5.24
(dd, JH1′,H2′â ) 11.1, JH1′,H2′R ) 5.0, 1H, H1′), 4.64-4.54 (m, 2H,
H5′), 4.45 (td, 1H, JH4′,H5′ ) 3.7, JH3′,H4′ ) 1.9, H4′), 2.36 (s, 3H),
Representative Epimerization Procedure: Epimerization of
4dRâ. To a solution of the bistoluoylated nucleoside 4dRâ (658
mg; 1.3 mmol) in 16 mL of CH2Cl2 trifluoroacetic acid (3 mL)
was added 500 mg of benzensulfonic acid. After 18 h of stirring at
40 °C the solution was cooled to 0 °C and triethylamine (10 mL)
was slowly added. The solvent was evaporated and the anomers
were separated on a silica gel column with cyclohexane/ethyl acetate
(19:1) to yield 385 mg of 4dâ as a colorless foam and 146 mg of
4dR as a colorless oil.
2.32 (s, 3H), 2.46 (ddd, JH2′R,H2′â ) 13.8, JH1′,H2′R ) 5.1, JH3′,H2′R
)
0.9, 1H, H2′R), 2.20 (s, 3H), 2.22-2.15 (m, 1H, H2′â). 13C NMR
(75 MHz, CDCl3): δ 166.4, 166.2, 144.1, 143.8, 140.6, 138.2,
129.8, 129.2, 129.2, 128.7, 128.4, 127.9, 127.1, 126.6, 123.1, 83.0,
81.0, 77.4, 64.8, 41.9, 21.7, 21.6, 21.4.
â-1′,2′-Dideoxy-3′,5′-di-O-toluoyl-1′-(3-biphenyl)ribofura-
nose (4dâ). HRMS(ESI): m/z C33H30O5Na+ calcd 529.1985 (M +
Na+), found 529.1985. 1H NMR (300 MHz, CDCl3): δ 7.99 (d, J
) 8.3, 2H), 7.93 (d, J ) 7.9, 2H), 7.64 (s, 1H), 7.54-7.47 (m,
3H), 7.40-7.31 (m, 5H), 7.27 (d, J ) 8.0, 2H), 7.15 (d, J ) 7.9,
2H), 5.64 (d, J ) 5.7, 1H, H3′), 5.32 (dd, JH1′,H2′â ) 11.1, JH1′,H2′R
) 5.1, 1H, H1′), 4.74 -4.64 (m, 2H, H5′), 4.58 -4.54 (m, 1H,
H4′), 2.58 (dd, JH2′R,H2′â ) 13.9, JH1′,H2′R ) 4.9, 1H, H2′R), 2.44 (s,
3H), 2.37 (s, 3H), 2.30 (ddd, JH2′â,H2′R ) 13.9, JH1′,H2′â ) 11.3,
JH3′,H2′â ) 6.0, 1H, H2′â). 13C NMR (75 MHz, CDCl3): δ 166.4,
166.2, 144.2, 143.8, 141.6, 141.2, 140.9, 129.8, 129.7, 129.2, 129.2,
129.0, 128.7, 127.3, 127.2, 127.0, 126.8, 125.0, 124.7, 83.2, 81.0,
77.4, 64.8, 42.0, 21.8, 21.7.
â-1′,2′-Dideoxy-3′,5′-di-O-toluoyl-1′-(2-anthracenyl)ribofura-
nose (4hâ). Epimerization of 4hR (574 mg; 1.08 mmol) yielded
161 mg of 4hâ (28%) as a colorless foam and 283 mg of of 4hR
+
(49%). HRMS(EI): m/z C35H30O5 calcd 530.2093 (M + Na+),
found 530.2093. 1H NMR (300 MHz, CDCl3): δ 8.39 (s, 1H), 8.30
(s, 1H), 8.04-7.95 (m, 8H), 7.49-7.44 (m, 3H), 7.30 (d, J ) 8.0,
2H), 7.19 (d, J ) 8.0, 2H), 5.69 (d, J ) 6.2, 1H, H3′), 5.46 (dd,
JH1′,H2′R ) 10.7, JH1′,H2′â ) 5.2, 1H, H1′), 4.80-4.63 (m, 2H, H5′),
4.63 (td, JH4′,H5′ ) 3.9, JH3′,H4′ ) 2.1, 1H, H4′), 2.64 (ddd, JH2′R,H2′â
) 13.7, JH1′,H2′R ) 5.2, JH3′,H2′R ) 0.8, 1H, H2′R), 2.45 (s, 3H),
2.37 (s, 3H), 2.43-2.35 (m, 1H, H2′â). 13C NMR (75 MHz,
CDCl3): δ 166.5, 166.3, 144.2, 143.8, 136.6, 131.9, 131.6, 131.3,
129.8, 129.8, 129.3, 129.2, 128.5, 128.4, 127.9, 127.2, 125.6, 125.0,
121.7, 82.6, 78.0, 77.1, 64.7, 40.7, 21.7, 21.7.
â-1′,2′-Dideoxy-3′,5′-ditoluoyl-1′-(1-phenanthrenyl)ribofura-
nose (4eâ). Epimerization of 4eR/â (173 mg; 0.33 mmol) yielded
100 mg of 4dâ (58%) as a colorless foam and 49 mg of mixed
General Deprotection Procedure: Synthesis of 2d. The
bistoluoylated nucleoside 4dâ (312 mg; 0.45 mmol) was dissolved
in 5 mL of dry methanol. Sodium methoxide (79 mg; 1.4 mmol)
was subsequently added. The solution was stirred at room temper-
ature for 4 h. For neutralization solid ammonium chloride was added
until the reaction mixture was weakly basic. The mixture was
poured into water and extracted with 20 mL ethyl acetate (3×).
The combined organic layers were dried over anhydrous MgSO4
and evaporated. The product was purified on silica gel flash
chromatography with CH2Cl2:MeOH(0-3%) as eluent to yield 116
mg (70%) of deprotected product 2d as a colorless oil.
+
fractions of 4eR/â (28%). HRMS(EI): m/z C35H30O5 calcd
1
530.2093 (M), found 530.2093. H NMR (300 MHz, CDCl3): δ
8.74-8.69 (m, 2H), 8.09 (d, J ) 8.2, 2H), 8.00-7.90 (m, 5H),
7.80-7.62 (m, 4H), 7.34 (d, J ) 7.9, 2H), 7.22 (d, J ) 7.9, 2H),
6.07 (dd, JH1′,H2′â ) 10.7 Hz, JH1′,H2′R ) 5.1 Hz, 1H), 5.73-5.71
(m, 1H, H3′), 4.80-4.78 (m, 2H, H5′), 4.72-4.70 (m, 1H, H4′),
2.90-2.84 (m, 1H, H2′R), 2.49 (s, 3H), 2.41 (s, 3H), 2.40-2.32
(m, 1H, H2′â). 13C NMR (75 MHz, CDCl3): δ 166.4, 166.2, 144.2,
143.8, 137.2, 131.4, 130.6, 130.4, 129.8, 129.7, 129.1, 128.7, 128.5,
127.2, 127.1, 127.0, 126.8, 126.6, 126.4, 123.0, 122.9, 122.4, 121.5,
82.7, 78.0, 77.2, 64.7, 41.0, 21.7, 21.6.
â-1′,2′-Dideoxy-1′-(3-biphenyl)ribofuranose (2d). HRMS-
(ESI): m/z C17H18O3Na+ calcd 293.1148 (M + Na+), found
1
â-1′′,2′′-Dideoxy-3′′,5′′-ditoluoyl-1′′-(R,S-[1,1′]binaphthylen-
4-yl)ribofuranose (4fâ). Epimerization of 4fR/â (220 mg; 0.36
mmol) yielded 105 mg of 4fâ (47%) as a colorless foam and 69
293.1151. H NMR (300 MHz, CDCl3): δ 7.59-7.29 (m, 9H),
5.22 (dd, JH1′,H2′â ) 10.2, JH1′,H2′R ) 5.7, 1H, H1′), 4.38 (ddd, 1H,
JH3′,H2′â ) 6.4, JH3′,H4′ ) 2.4, JH3′,H2′R ) 2.4, H3′, 1H), 4.02 (td,
1H, JH4′,H5′ ) 4.9, JH3′,H4′ ) 3.0, H4′), 3.74 (m, 2H, H5′), 2.95 (br,
+
mg of of 2fR (32%). HRMS(EI): m/z C41H34O5 calcd 606.2406
(M), found 606.2403. 1H NMR (300 MHz, CDCl3): δ 8.15-7.18
(m, 21H), 6. 10 (dd, JH1′,H2′R ) 10.2, JH1′,H2′â ) 4.8, 1H, H1′), 5.76-
5.72 (m, 1H, H3′), 4.81-4.70 (m, 3H, H5′, H4′), 2.95-2.88 (m,
1H, H2′R), 2.46 (s, 3H), 2.56-2.44 (m, 1H, H2′â), 2.40 (s, 1.6H),
2.36 (s, 1.4H). 13C NMR (75 MHz, CDCl3): δ 166.5, 166.3, 144.3,
2H, -OH), 2.26 (ddd, JH2′R,H2′â ) 13.2, JH1′,H2′R ) 5.7, JH3′,H2′R )
2.1, 1H, H2′R), 2.03 (ddd, JH2′R,H2′â ) 13.2, JH1′,H2′â ) 10.2, JH3′,H2′â
) 6.3, 1H, H2′â). 13C NMR: (75 MHz, CDCl3): δ 141.7, 141.5,
140.1, 129.0, 128.8, 127.4, 127.2, 126.7, 125.0, 87.4, 80.2, 73.6,
63.4, 43.7.
J. Org. Chem, Vol. 72, No. 23, 2007 8817

Hainke et al.
â-1′,2′-Dideoxy-1′-(3-tolyl)ribofuranose (2b). Compound 4bâ
(333 mg; 0.75 mmol) was deprotected to yield 2b (143 mg; 92%)
as a colorless oil. HRMS(EI): m/z C12H15O3+ calcd 207.1018 (M),
3.74 (m, 2H, H5′), 2.29 (dd, JH2′R,H2′â ) 13.1, JH1′,H2′R ) 5.7, 1H,
H2′R), 2.06 (ddd, JH2′R,H2′â )12.9, JH1′,H2′â ) 10.6, JH3′,H2′â ) 6.1,
1H, H2′â). 13C NMR (75 MHz, MeOH-d4): δ 142.5, 141.3, 140.1,
135.1, 133.8, 130.0, 129.4, 128.9, 128.5, 128.4, 126.7, 126.5, 126.3,
125.5, 89.4, 81.9, 74.6, 64.2, 45.0.
1
found 207.1018. H NMR (300 MHz, CDCl3): δ 7.28-7.10 (m,
4H), 5.13 (dd, JH1′,H2′â ) 10.2, JH1′,H2′R ) 5.6, 1H, H1′), 4.38 (ddd,
1H, JH3′,H2′â ) 6.4, JH3′,H4′ ) 2.2, JH3′,H2′R ) 2.2, H3′, 1H), 4.00
(td, 1H, JH4′,H5′ ) 4.8, JH3′,H4′ ) 3.0, H4′), 3.80-3.70 (m, 2H, H5′),
3.05 (br, 1H, -OH), 2.83 (br, 1H, -OH), 2.40 (s, 3H), 2.23 (ddd,
JH2′R,H2′â )13.3, JH1′,H2′R ) 5.7, JH3′,H2′R ) 2.0, 1H, H2′R), 2.02
(ddd, JH2′R,H2′â )13.3, JH1′,H2′â ) 10.2, JH3′,H2′ â ) 6.3, 1H, H2′â).
13C NMR (75 MHz, CDCl3): δ 141.0, 138.2, 128.6, 128.4, 126.8,
123.1, 87.3, 80.2, 73.6, 63.4, 43.6, 21.4.
â-1′,2′-Dideoxy-1′-(2-anthracenyl)ribofuranose (2h).14 Com-
pound 4hâ (316 mg; 0.57 mmol) was deprotected to yield 2h (99
mg; 57%) as a yellow solid. Mp >170 °C dec. HRMS(EI): m/z
C19H18O3+ calcd 294.1256 (M + Na+), found 294.1256. 1H NMR
(300 MHz, CDCl3/MeOH 3:1): δ 8.32 (s, 2H, 7.93-7.89 (m, 4H),
7.40-7.35 (m, 3H), 5.28 (dd, JH1′,H2′â ) 10.2, JH1′,H2′R ) 5.6, 1H,
H1′), 4.33 (ddd, 1H, JH3′,H2′â ) 5.5, JH3′,H4′ ) 2.2, JH3′,H2′R ) 2.2,
H3′, 1H), 3.98 (td, 1H, JH4′,H5′ ) 5.1, JH3′,H4′ ) 2.8, H4′), 3.70 (m,
â-1′,2′-Dideoxy-1′-(2-biphenyl)ribofuranose (2câ). Compound
4c (490 mg; 0.97 mmol) was deprotected to yield 2cRâ (211 mg;
81%) as a colorless oil. Separation with preparative HPLC afforded
2cRâ (100 mg) and 2cRâ (80 mg). HPLC: tr ) 23.2 min. HRMS-
(ESI): m/z C17H18O3Na+ calcd 293.1148 (M + Na+), found
293.1150. 1H NMR (300 MHz, CDCl3): δ 7.68 (dd, J ) 6.2, 0.8,
1H), 7.38-7.19 (m, 9H), 5.13 (dd, JH1′,H2′â ) 8.0, JH1′,H2′R ) 8.0,
2H, H5′), 2.25 (ddd, JH2′R,H2′â ) 13.2, JH1′,H2′R ) 5.7, JH3′,H2′R
)
1.9, 1H, H2′R), 2.11 (ddd, JH2′R, H2′â ) 13.2, JH1′,H2′â ) 10.3, JH3′,H2′â
) 6.2, 1H, H2′â). 13C NMR (75 MHz, CDCl3/MeOH 6:1): δ 137.8,
131.6, 131.4, 131.0, 131.0, 128.3, 127.8, 127.7, 125.9, 125.7, 125.1,
125.0, 124.5, 123.5, 87.4, 80.2, 72.8, 62.7, 42.8.
Procedure for Gilman-Cuprate Mediated Synthesis of O-
Aryl-glycosides: Synthesis of 5bRâ. In a dry argon-flushed flask
2-iodoanthracene (240 mg; 0.79 mmol) was added to 10 mL of
dry THF and the mixture was cooled to -78 °C. With use of a
glass syringe, t-BuLi in pentane (1.05 mL; 1.5 M; 1.58 mmol) was
added dropwise and the solution was stirred for 15 min. After
addition of copper iodide (75 mg; 2.95 mmol) the solution was
allowed to warm up while the CuI dissolved. After cooling to
-40 °C 1 (730 mg; 1.87 mmol) was subsequently added. The argon
was removed at reduced pressure and the flask was filled with air.
The mixture was stirred for 18 h. For workup a 10% aqueous
solution of NH4Cl was added followed by extraction with 20 mL
of CH2Cl2 (3×). The combined organic layers were washed with a
saturated aqueous solution of NaHCO3 (3×) and brine and dried
over anhydrous MgSO4 and solvent was removed under reduced
pressure. The product was purified on a silica gel column with
cyclohexane:ethyl acetate (19:1) to yield 86 mg (64%) of 5bR as
a colorless oil and 22 mg (16%) of 5bâ as a colorless oil.
R-1′,2′-Dideoxy-1′-(2-anthracenyloxy)ribofuranose (5bR). HRM-
S(ESI): m/z C35H30O6Na+ calcd 569.1935 (M + Na+), found
1H, H1′), 4.21 (ddd, 1H, JH3′,H2′â) 4.4, JH3′,H2′R ) 4.4, JH3′,H4′
)
4.0, H3′, 1H), 3.72 (td, 1H, JH4′,H5′ ) 4.0, JH3′,H4′ ) 4.0, H4′), 3.68-
3.58 (m, 2H, H5′), 2.78 (br, 2H, -OH), 1.95-1.92 (m, 2H, H2′).
13C NMR (75 MHz, CDCl3): δ 141.2, 140.7, 138.6, 130.0, 129.2,
128.1, 127.8, 127.4, 127.2, 125.8, 86.6, 76.9, 73.4, 63.1, 44.0.
R-1′,2′-Dideoxy-1′-(2-biphenyl)ribofuranose (2cR). HPLC: tr
) 24.3 min. HRMS(ESI): m/z C17H18O3Na+ calcd 293.1148 (M
1
+ Na+), found 293.1149. H NMR (300 MHz, CDCl3): δ 7.68
(dd, J ) 6.2, 0.8, 1H), 7.39-7.16 (m, 8H), 5.01 (dd, J ) 9.2, 6.4,
1H, H1′), 4.20 (ddd, 1H, J ) 7.2, 7.2, 7.2, H3′, 1H), 3.98 (td, 1H,
JH4′,H5′ ) 4.4, JH3′,H4′ ) 6.4, H4′), 3.66-3.52 (m, 2H, H5′), 2.60
(br, 2H, -OH), 2.36 (ddd, JH2′R,H2′â )13.2, JH1′,H2′R ) 6.5, JH3′,H2′R
) 6.5, 1H, H2′R), 1.90 (ddd, JH2′R,H2′â )12.4, JH1′,H2′â ) 9.6, JH3′,H2′â
) 8.0, 1H, H2′â). 13C NMR (75 MHz, CDCl3): δ 140.8, 140.7,
139.9, 129.9, 129.2, 128.1, 127.9, 127.2, 127.1, 125.6, 84.9, 76.5,
72.6, 62.2, 43.6.
â-1′,2′-Dideoxy-1′-(1-phenanthrenyl)ribofuranose (2e). Com-
pound 4eâ (224 mg; 0.42 mmol) was deprotected to yield 2e (93
mg; 79%) as a colorless solid. Mp 163-165 °C. HRMS(ESI): m/z
C19H18O3Na+ calcd 317.1144 (M + Na+), found 317.1148. 1H NMR
(300 MHz, DMSO-d6): δ 8.84 (d, J ) 7.8, 1H), 8.78 (d, J ) 8.3,
1H), 8.02-7.98 (m, 2H), 7.90 (d, J ) 7.6, 1H), 7.87 (d, J ) 5.7,
1H), 7.73-7.63 (m, 3H), 5.82 (dd, JH1′,H2′â ) 10.1, JH1′,H2′R ) 5.5,
1H, H1′), 5.20 (d, J ) 4.3, 1H, OH), 4.85 (t, J ) 5.6, 1H, OH),
4.25 (m, 1H, H3′), 3.93 (td, 1H, JH4′,H5′ ) 5.1, JH3′,H4′ ) 2.6, H4′),
3.58 (m, 2H, H5′), 2.39 (ddd, JH2′R,H2′â )12.7, JH1′,H2′R ) 5.6, JH3′,H2′R
) 1.9, 1H, H2′R), 2.11 (ddd, JH2′R,H2′â )12.7, JH1′,H2′â ) 10.2,
JH3′,H2′â ) 5.9, 1H, H2′â). 13C NMR (75 MHz, DMSO-d6): δ 139.7,
131.5, 130.5, 130.2, 128.8, 127.4, 127.3, 126.9, 123.6, 122.5, 122.4,
88.0, 76.6, 72.8, 62.8, 43.3.
1
569.1935. H NMR (300 MHz, CDCl3): δ 8.38 (s, 1H), 8.33 (s,
1H), 8.06 (d, J ) 8.2, 2H), 8.01-7.93 (m, 5H), 7.60 (d, J ) 2.3,
1H), 7.50-7.40 (m, 2H), 7.33-7.22 (m, 6H), 6.22 (d, J ) 4.7,
1H, H1′), 5.65 (ddd, J ) 7.4, 2.9, 1.8, 1H, H3′), 4.80 (td, 1H, J )
6.9, 3.6, H4′), 4.73-4.61 (m, 2H, H5′), 2.81 (ddd, J ) 14.4, 7.4,
5.2, 1H, H2′â), 2.67 (d, J ) 14.7, 1H, H2′R), 2.47 (s, 3H), 2.44 (s,
3H). 13C NMR (75 MHz, CDCl3): δ 166.5, 166.3, 154.1, 144.1,
144.0, 132.5, 132.1, 130.6, 129.9, 129.9, 129.7, 129.2, 128.6, 128.2,
127.7, 127.0, 126.1, 125.5, 124.8, 124.8, 124.6, 120.7, 102.2, 82.7,
74.6, 64.3, 39.6, 21.7, 21.7.
â-1′,2′-Dideoxy-1′-(2-anthracenyloxy)ribofuranose (5bâ). HRM-
â-1′′,2′′-Dideoxy-1′′-(R,S-[1,1′]binaphthylen-4-yl)ribofura-
nose (2f). Compound 4fâ (173 mg; 0.34 mmol) was deprotected
to yield 2f (73 mg; 70%) as a white solid. Mp 164-166 °C. HRMS-
(EI): m/z C25H22O3+ calcd 370.1568 (M), found 370.1568. 1H NMR
(300 MHz, MeOH-d4): δ 8.11 (d, J ) 8.4, 1H), 7.89-7.81 (m,
3H), 7.52-7.32 (m, 5H), 7.89-7.81 (m, 3H), 7.24-7.13 (m, 4H),
5.97-5.91 (m, 1H, H1′′), 4.39-4.34 (ddd, J ) 4.7, 4.7, 2.3, 1H,
H3′′), 4.08-4.04 (ddd, J ) 5.2, 5.1, 2.9, 1H, H4′′), 3.79-3.68 (m,
S(ESI): m/z C35H30O6Na+ calcd 569.1935 (M + Na+), found
1
569.1934. H NMR (300 MHz, CDCl3): δ 8.34 (s, 1H), 8.28 (s,
1H), 8.01-7.82 (m, 6H), 7.58 (d, J ) 2.3, 1H), 7.49-7.41 (m,
2H), 7.31-7.20 (m, 3H), 7.15 (dd, J ) 9.1, 2.4, 1H), 7.06 (d, J )
7.9, 2H), 6.24 (dd, JH1′,H2′R ) 5.6, JH1′,H2′â ) 2.5, 1H, H1′), 5.69
(ddd, J ) 7.2, 4.5, 3.0, 1H, H3′), 4.75 (td, JH4′,H5′ ) 5.6, JH3′,H4′
)
3.0, 1H, H4′), 4.67-4.50 (m, 2H, H5′), 2.98 (ddd, J ) 14.4, 7.1,
2.5, 1H, H2′), 2.43-2.35 (ddd, J ) 14.4, 5.6, 4.7, 1H, H2′), 2.46
(s, 3H), 2.32 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 166.2, 166.2,
154.1, 144.2, 143.6, 132.4, 132.1, 130.6, 129.8, 129.7, 129.2, 128.9,
128.6, 128.2, 127.7, 126.9, 126.8, 126.0, 125.5, 124.8, 124.6, 120.5,
102.7, 82.7, 75.3, 64.5, 39.6, 21.7, 21.6.
2H, H5′′), 2.56-2.47 (m, 1H, H2′′), 2.10-1.97 (m, 1H, H2′′). 13
C
NMR (75 MHz, MeOH-d4): δ 139.9, 139.4, 139.1, 135.1, 134.2,
132.0, 129.3, 129.0, 128.9, 128.8, 128.5, 128.2, 127.4, 127.0, 126.9,
126.6, 126.4, 124.6, 122.8, 88.9, 78.3, 78.3, 74.4, 64.1, 44.1, 44.1.
â-1′,2′-Dideoxy-1′-(2-(7-phenyl)naphthyl)ribofuranose (2g).
Compound 4gâ (190 mg, 0.34 mmol) was deprotected to yield 2g
(101 mg; 92%) as a white solid. Mp 125-127 °C. HRMS(ESI):
m/z C21H20O3Na+ calcd 343.1305 (M + Na+), found 343.1307. 1H
NMR (300 MHz, MeOH-d4): δ 8.06 (s,1H), 7.94 (s,1H), 7.90 (d,
J ) 8.5, 1H), 7.85 (d, J ) 8.4, 1H), 7.76-7.71 (m, 3H), 7.54-
7.33 (m, 4H), 5.31 (dd, JH1′,H2′â ) 10.5, JH1′,H2′R ) 5.4, 1H, H1′),
4.43 (m, H3′, 1H), 4.03 (td, 1H, JH4′,H5′ ) 5.0, JH3′,H4′ ) 2.4, H4′),
R-1′,2′-Dideoxy-3′,5′-di-O-toluoyl-1′-(3-tolyloxy)ribofura-
nose (5aR). Compound 5aR was synthesized from 1 (100 mg; 0.26
mmol) to afford 5aR (77 mg; 62%) as a colorless oil. HRMS-
(ESI): m/z C28H28O6Na+ calcd 483.1778 (M + Na+), found
1
483.1778. H NMR (300 MHz, CDCl3): δ 8.01 (d, J ) 8.4, 2H),
7.94 (d, J ) 8.1, 2H), 7.30-7.18 (m, 5H), 6.92 (s, 1H, H2), 6.91
(d, 1H), 6.85 (d, 1H), 6.01 (d, J ) 4.5, 1H, H1′), 5.60-5.56 (m,
1H, H3′), 4.72-4.69 (m, 1H, H4′), 4.62-4.59 (m, 2H, H5′), 2.96
8818 J. Org. Chem., Vol. 72, No. 23, 2007

Synthesis of C-Aryl-Nucleosides and O-Aryl-Glycosides
(ddd, JH2′R,H2′â ) 14.1, JH1′,H2′â ) 7.0, JH3′,H2′â ) 7.0, 1H, H2′â),
2.54 (ddd, JH2′â,H2′R) 14.1, J ) 0.9, 1H, H2′ R), 2.45 (s, 3H), 2.44
(s, 3H), 2.36 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 166.2, 166.1,
156.9, 144.1, 143.6, 139.4, 129.8, 129.8, 129.2, 129.0, 127.1, 126.8,
122.9, 117.4, 113.6, 102.3, 82.5, 77.5, 64.6, 39.5, 21.7, 21.7, 21.5.
â-1′,2′-Dideoxy-3′,5′-di-O-toluoyl-1′-(3-tolyloxy)ribofura-
nose (5aâ). Compound 5aâ was synthesized from 1 (100 mg; 0.26
mmol) to afford 5aâ (31 mg; 25%) as a colorless oil. HRMS(ESI):
m/z C28H28O6Na+ calcd 483.1778 (M + Na+), found 483.1778. 1H
NMR (400 MHz, CDCl3): δ 7.91 (d, J ) 8.3, 2H), 7.88 (d, J )
8.0, 2H), 7.22 (d, J ) 8.0, 2H), 7.17-7.10 (m, 3H), 6.83 (s, 1H,
H2), 6.82 (d, J ) 8.0, 1H, H6), 6.78 (d, J ) 7.2, 1H, H5), 5.98
(dd, JH1′,H2′R ) 6.4, JH1′,H2′â ) 3.2, 1H, H1′), 5.70 (ddd, J ) 7.2,
4.4, 3.2, 1H, H3′), 4.65-4.60 (m, 1H, H4′), 4.56-4.43 (m, 2H,
H5′), 2.82 (dd, JH2′R,H2′â ) 14.4, J ) 6.8, JH1′,H2′â ) 2.4, 1H, H2′â),
2.54 (ddd, JH2′â,H2′R ) 14.4, JH1′,H2′R ) 5.6, J ) 4.4, 1H, H2′R),
2.40 (s, 3H), 2.37 (s, 3H), 2.28 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ 165.5, 156.7, 139.9, 139.8, 139.6, 131.2, 131.1, 129.4,
129.3, 128.9, 128.6, 128.1, 123.0, 117.2, 113.6, 112.3, 102.1, 82.2,
75.0, 64.5, 39.4, 21.5, 21.5, 21.4.
Acknowledgment. Support from Deutsche Forschungsge-
meinschaft and Schering AG is acknowledged. The authors are
grateful for donations of chemicals from Bayer Services GmbH
& Co. OHG and BASF AG.
Supporting Information Available: General procedures and
NMR spectra, including the 1H-1H NOESY spectra of compounds
2bâ, 2câ, 2cR, 4dâ, 4fâ, 2g, 6aâ, and 6bR. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO7016185
J. Org. Chem, Vol. 72, No. 23, 2007 8819